Genetically Predicted Immune Cell-Mediated Effect of Lipid Metabolism on Allergic Diseases: A Two-Step, Mediation Mendelian Randomization Study

Introduction: An increasing number of studies have demonstrated that dynamic changes in lipid species can affect allergic diseases; however, the causal relationship and mediating role of immune cells remain unclear. Methods: We conducted a bidirectional two-sample mendelian randomization (MR) analysis using genome-wide association study (GWAS) data on 179 lipid species (n = 7,174) and three types of allergic diseases including allergic rhinitis (AR) (n = 370,158), allergic asthma (n = 219,753), and allergic conjunctivitis (n = 377,277). The principal model used was the inverse variance-weighted approach, and a series of sensitivity analyses were conducted to ensure the robustness of the results. We used a two-step MR approach to assess whether the causal effect was mediated by immune cells (n = 3,757). Results: Sterol ester and sphingomyelin played pathogenic roles in allergic asthma, AR, and allergic conjunctivitis; however, the effective subtypes differed. Among them, CD45RA⁻ CD4⁺ mature T cells and CCR2 on CD14⁺ CD16⁺ monocytes affected the promoting impact of sterol ester’s metabolism on allergic asthma and AR with different mediating proportions, while the role of sphingomyelin may not involve the immune cells. Moreover, we observed that HLA-DR on CD33⁻ HLA DR⁺ myeloid cells, CD11b on CD66b⁺⁺ myeloid cells, and IgD⁺ CD38⁻ B cells played the most mediating effect of phosphatidylethanolamine (O−18:2_20:4) in allergic asthma, phosphatidylinositol (16:0_18:1) in AR, and phosphatidylethanolamine (18:0_18:2) in allergic conjunctivitis. Conclusion: This MR study provides evidence for specific lipid species associated with the risk of allergic diseases, especially sterol esters, and identifies the immune cells that mediate this causal relationship.